Behavioral sensitization, the enhanced motor-stimulant response that occurs with repeated, intermittent exposure to cocaine, has been proposed to play a role in drug craving and relapse. An increased understanding of the mechanisms involved in the development of sensitization may lead to improved pharmacotherapies for drug addiction. It has been suggested that cocaine-induced changes in the ventral tegmental area (VIA) and nucleus accumbens are involved in the initiation and expression of sensitization, respectively. However, recent studies do not entirely support this hypothesis. Thus, the present proposal will test the hypothesis that sensitization results from a decrease in dopamine-mediated glutamate transmission from the medial prefrontal cortex (mPFC). We have reported that depletion of dopamine in the mPFC by 6-hydroxydopamine lesions enhances the motor-stimulant response to cocaine. Follow up studies will determine whether these lesions also enhance glutamate transmission in the mPFC and dopamine and glutamate transmission in regions innervated by the mPFC such as the VTA and nucleus accumbens. A second set of studies will determine whether sensitization to cocaine is associated with changes in dopamine and glutamate transmission in the mPFC using in vivo microdialysis. The temporal relation of neurochemical changes in the mPFC, compared with those previously shown in the nucleus accumbens, will also be assessed. The role of mPFC dopamine in the development of sensitization will be further examined by determining the effects of site specific injections of dopamine receptor agonists or antagonists into the mPFC on behavioral and neurochemical responses to cocaine. Preliminary data suggest that sensitization to cocaine may result from a decrease in dopamine receptor function in the mPFC. To determine this, the effects of repeated cocaine exposure on dopamine receptor regulation of adenylyl cyclase activity in the mPFC will be examined. Results of these studies should provide a better understanding of the role the mPFC plays in the development of sensitization to cocaine.